IL-13 and hepatic gluconeogenesis

When I started learning about immunology I held a conviction that the immunity serves only to combat infections and pathogens. Perhaps the major change I have acquired in my understanding of immune processes is that the function of the immune system could be more permeating and extend to broader activities than just the defense. What we call the immune system works in situations well beyond the strict response to pathogenic organisms. It does not necessarily fight foreign entities as it may accommodate them (in case of microbiota) and also it has the intriguing links with the metabolism. I have found a publication that adds an interesting voice in support of such more general role of the immune system. It turns out that the cytokine IL-13 which is an important player in Th2 branch of immunity may influence how our body maintains one of the most important metabolic indicators.

The link: http://www.jci.org/articles/view/64941

Authors show data that mice deleted for gene encoding IL-13 display the impaired control of glucose level in the blood. Such defect appears to be a systemic one since it comprises both the increased production of glucose by liver cells as well as the reduced glucose uptake by muscles. Additionally, investigators delve into the molecular mechanism that underlies the IL-13-dependent control over the glucose production in the liver. It turns out that the transcription factor STAT3 could be the mediator between IL-13 signaling and genes involved in hepatic gluconeogenesis. Other than that authors attempt to identify the cellular population which may be responsible for the release of IL-13 in the liver and suggest that these could be NKT cells.

I am not really sure if it is sound to speculate in such way but there is at least the theoretical possibility that the exposure to parasites that provoke Th2-skewed response (like helminths) could protect from developing type II diabetes. The only problem is that relatively benign organisms inhabit the gastrointestinal tract and their influence may not extend to the liver whereas those that infect systemically (like Schistosoma mansoni) are too dangerous to be treated as a therapeutic agent. However, schistosome eggs are already applied as support in the treatment of excessive gut inflammation. May they be helpful in the regulation of glucose level?

Stanya KJ, Jacobi D, Liu S, Bhargava P, Dai L, Gangl MR, Inouye K, Barlow JL, Ji Y, Mizgerd JP, Qi L, Shi H, McKenzie AN, & Lee CH (2013). Direct control of hepatic glucose production by interleukin-13 in mice. The Journal of clinical investigation, 123 (1), 261-71 PMID: 23257358

Advertisements

Schistosoma mansoni evacuates its eggs through Peyer’s patches

Schistosomes are parasitic worms that live in the blood and have a complicated life cycle. The sexual form inhabits vertebrates (humans included) whereas the other stages infest fresh water snails. Adult worms tend to chronically infect their host (sometimes for many years) but for the propagation they have to be able to release their eggs to the outer environment. These blood parasites are remarkably invisible to the immune system; however, their eggs are known to induce the immune response. How such ability may connect to the propagation issue is the subject of the recent publication.

The link: http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003063

Authors study how Schistosoma mansoni, which is an endemic human parasite present in many tropical regions of the world, may excrete its eggs through the intestinal barrier (schistosome species vary between utilization of the intestinal and urinary tracts as the evacuation routes for eggs). It looks like to this end the parasite uses the lymphatic structures encountered in the lower portion of the small intestine – Peyer’s patches. The presence of mature schistosome eggs is apparently able to remodel the vasculature around Peyer’s patches and introduce changes to the cellularity of these intestinal lymphatic structures. Moreover and crucially, in the strain of mice that harbors no Peyer’s patches the egg excretion is visibly reduced and more eggs appear to be backwashed into the host tissue where they form granulomas.

For a number of years schistosome eggs have been hyped as the “taming agent” of the over-reacting immune system. It is well known that they possess the modulatory influences over a number of inflammatory conditions that afflict the gastrointestinal tract. I wonder if such an ability to modulate may be due to the described peculiar interaction of schistosome eggs with their hosts’ Peyer’s patches. From the schistosome point of view eggs need to get out. Thus the parasite may have evolved to drive the immune reaction to its eggs because of the necessity to utilize immune structures for the egg excretion.

Joseph D. Turner,Priyanka Narang,Mark C. Coles,Adrian P. Mountford (2012). Blood Flukes Exploit Peyer’s Patch Lymphoid Tissue to Facilitate Transmission from the Mammalian Host PLOS Pathogens

Memory CD4 T cells and the neonatal gut

I have found a short paper on the potential mechanism of how HIV virus may be transmitted between mother and child. I think it is interesting because it not only provides the information which may be useful for a given pathology but it also poses some questions as to the basic immunology processes. The main theme of the paper is the quest for HIV targets among neonatal CD4 T cells. As it is known the virus tends to infect memory CD4 T cells but these cells are practically absent in the cord blood. Thus authors inspect neonatal CD4 T populations from various anatomical compartments and find that CD4 T cells bearing a memory marker and HIV co-receptor abound at the intestinal mucosa.

The link: http://bloodjournal.hematologylibrary.org/content/120/22/4383.abstract

CD4 T cells collected for this study derive from children born to healthy mothers therefore this report asks only about the potential mechanism of mother to child transmission. Authors follow CD4 T cells that bear also CD45RO (which is a marker of memory state) and CD5 (HIV uses this molecule as a co-receptor to infect an individual cell – only CD5-tropic strains tend to become transmitted form mother to child). The main conclusion of this publication is that the population of CD4+CD45RO+CD5+cells (the potential HIV target according to the current state of knowledge) exists at the neonatal gut mucosa but not in the lymph nodes, spleen or blood. Additionally, around half of this intestinal memory CD4+CD45RO+CD5population appears to be differentiated into Th17 phenotype since these cells express RORγt transcription factor and CCR6.  In an in vitro experiment investigators also show that neonatal CD4 T cells from the gut are more susceptible to HIV infection than CD4 T cells from the lymph nodes or blood.

Based on obtained data authors propose a model of how HIV gets transmitted from mother to child. According to them the virus may take the oral route of transmition by the ingestion of infected body fluids during the delivery or milk shortly afterwards. I lack the clinical knowledge to critically evaluate such proposal. But I have more basic question instead. This paper not only shows the presence of memory CD4 T cells population at the neonatal gut mucosa but it also provides the evidence that these memory cells underwent substantial clonal expansion that must have happened in utero. I would like to know more details on the nature of antigenic challenge that underlies such prenatal activation of the adaptive immune system.

Bunders MJ, van der Loos CM, Klarenbeek PL, van Hamme JL, Boer K, Wilde JC, de Vries N, van Lier RA, Kootstra N, Pals ST, & Kuijpers TW (2012). Memory CD4+CCR5+ T cells are abundantly present in the gut of newborn infants to facilitate mother-to-child transmission of HIV-1. Blood, 120 (22), 4383-90 PMID: 23033270

First prime and then pull – the novel immunization approach

Some areas of our body enjoy a special status as far as the immune reaction is concerned. Anatomical entities like the gut or female genital tract as well as other mucosal surfaces do not support the same extend of protective response compared to many non-mucosal tissues. This exclusion is crucial to avoid the unwanted inflammation in places that are regularly exposed to the outer environment but sometimes it may present a problem when there is the need to elicit the strong protective response at such privileged site. I have found an interesting report which applies the novel vaccination strategy aimed to enhance the protection against herpes simplex virus 2 which being the virus transmitted through the contact with infected body fluids often enters the body through the genital organs. The innovation that this report introduces consists of double treatment (“prime and pull”) which bypasses the restrictive entry of memory T cells into the vaginal mucosa.

The link: http://www.nature.com/nature/journal/v491/n7424/full/nature11522.html

The mentioned “prime and pull” strategy is the subcutaneous immunization with an attenuated strain of HSV-2 (prime) which is followed by the topical application of chemokines CXCL9 and CXCL10 to the vaginal mucosa (pull). Authors follow the localization of CD8 T cells that recognize an epitope within one of HSV-2 glycoproteins and activated CD4 T cells to show that the distal immunization event plus the localized chemokine treatment provokes the significant recruitment of activated lymphocytes to the vagina whereas the immunization alone has much weaker effect. Interestingly, this recruitment is specific to CD4 and CD8 lymphocytes and does not encompass other cell types that express the relevant chemokine receptor CXCR3.

Is the “prime and pull” approach able to provide the longstanding and reliable protection? Data demonstrate that CD8 T cells (but not CD4 T cells) are retained at vaginal mucosa after the primary response period is over. Most importantly the “prime and pull” treatment may be indeed superior in enforcing the better protective immunity to HSV-2 challenge than the immunization alone. Investigators also ask about the mechanism by which the protection is delivered by the “prime and pull” strategy. It appears that this application can prevent the virus from entering the nervous system where HSV-2 propagates past the mucosal stage of infection.

What will be the future of “prime and pull”, though? The pros are obvious – there is the simple method to enhance the mucosal migration of protective lymphocytes without the “ugly face” of immunity which in this case would be the excessive inflammation at the sensitive anatomical location. Authors speculate about the future applications ranging from HIV protection to solid tumors treatment. The method itself may also be developed as in the discussed paper it provides the optimal protection only in conjunction with the adoptive transfer of virus-specific lymphocytes. The “pull” works as well with the endogenous population of CD8 T cells; however, the protection is suboptimal in such scenario. I will follow this story.

Shin H, & Iwasaki A (2012). A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature, 491 (7424), 463-467 PMID: 23075848

Non-pathogenic SIV infection and type-I interferon signaling

How monkeys or apes respond to the challenge of lentiviral immunodeficiency viruses varies across different primate species. Some primates like rhesuses are similar to humans because following SIV infection they develop the AIDS-like disease with all the characteristic features of progressive immune destruction. However, there are other species that do not display such aggravated pathology. African sooty mangabeys are the best studied example among these AIDS-refractory animals. Infected sooty mangabeys do not clear the virus but seem to have adapted to live with it. Such infection lasts for life but it is the relatively mild condition without the continuous depletion of memory CD4 T cells and the chronic immune activation that are associated with human or simian AIDS. The current clinical efforts in humans aim at the reduction of damage caused by the infection and slowing down the progression to AIDS. Thus the detailed knowledge of how AIDS-refractory species achieve their status might be instructive and there is the respective research avenue devoted to studying these species. I have found the publication that looks at the role of type-I interferon signaling during the chronic phase of SIV infection in a species that does not progress to AIDS.

The link: http://bloodjournal.hematologylibrary.org/content/119/24/5750.abstract

Authors attempt to clarify the interactions between the presence of the augmented type-I interferon signaling and the immune response in the chronic phase of SIV infection. Their rationale is simple – since the up-regulation of interferon signature genes correlates with HIV/SIV infections that progress to AIDS, so what may happen if artificially boost the expression of these genes during the non-pathogenic SIV infection? To this end they choose several naturally infected sooty mangabeys and subject them to the treatment with type-I IFN agonist which procures strong but transient enhancement in the expression of interferon signature genes.

To obtain the answer to their question investigators focus on how the increased type-I interferon signaling influences several relevant immune parameters. Acquired data are compared to the baseline values that were observed before the onset of treatment (no control group is included in this research due to availability reasons). The studied parameters comprise the range of CD4 T cells depletion (an indicator of the immune system impairment), the activation and proliferation levels of CD4 T cells (indicators of the chronic immune activation) as well as the intensity of anti-SIV CD8 response.

The take-home message from this report is that the administration of type-I interferon agonist does not impact any of immune parameters that were tested but it only brings down temporarily the viremia level (after all, type-I IFN is regarded as the anti-virus defensive molecule). What does it mean for the understanding of non-pathogenic SIV infection? The mechanisms responsible for the AIDS-refractory status are most probably complex, robust and might not depend on just one particular pathway.

Vanderford TH, Slichter C, Rogers KA, Lawson BO, Obaede R, Else J, Villinger F, Bosinger SE, & Silvestri G (2012). Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood, 119 (24), 5750-7 PMID: 22550346

Enter the mycobiota

I have found the publication that focus on pretty much unexplored subject which is the presence and role of commensal fungi in the mammalian gastrointestinal tract. As far as I know there is no information on whether the intestinal fungi community (similarly the bacterial microbiome) has any influence on the basic metabolic functions of their hosts. The discussed paper does not provide such knowledge either. Instead it attempts to establish a link between the increased susceptibility to colitis and the inability to respond properly to fungal wall components (through the lack of the innate receptor Dectin-1) as well as it makes the initial analysis of murine mycobiome. Although it is probably too early to draw such conclusion, my impressions are that there might be differences in the very basics rules of cohabitation between mammals and intestinal fungi compared to mammals/commensal bacteria interactions.

The link: http://www.sciencemag.org/content/336/6086/1314.abstract

Authors confirm the presence of fungi in the gastrointestinal tract with two methods – the first detects the specific fungal RNA whereas the second visualizes fungal cells with soluble Dectin-1 probe (Dectin-1 recognizes β-1,3-glucans from fungal cell wall). The biggest fungal concentration is found in the colon which is also the place where commensal bacteria reach their highest density. However, the bulk of data is devoted to the analysis how the absence of Dectin-1 (which as mentioned above is the fungi-specific innate receptor linked to the inflammasome pathway) may influence the colitis development. The most important finding in that aspect is that the lack of Dectin-1 procures significantly worse colitis outcome in the mouse model that applies DSS-induced injury. Also the polymorphism in human gene encoding Dectin-1 is linked to the severe form of disease recognized as MRUC (medically refractory ulcerative colitis).

The publication contains other interesting data that allow very initial comparison between the characteristics of microbiome and mycobiome. One of important terms that describe a specific interaction between intestinal bacteria and their host is “dysbiosis”. The dysbiosis occurs when the gastrointestinal tract holds the abnormal microflora composition which appears to be able to influence the predisposition to maladies like gut inflammation or metabolic syndrome malfunctions. An interesting example of dysbiosis develops when animals are deficient for the innate receptor that recognizes bacterial flagellin (TLR5) which is a dominant immune activator in the gut. Remarkably, in some cases this pathogenic microflora setup has been shown to be transferable between different specimens as the sheer cohabitation of experimental animals (which is meant to expose them to each other microbiota) may change their susceptibility to certain diseases (consult the following report for an example: Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature; 2012. 482: 179-85). Authors test whether the absence of Dectin-1 could trigger any disease-facilitating microflora variations by crisscross transferring of microflora (not discriminating between bacteria and fungi) from either wild type animals or animals with Dectin-1 deficiency. However, such exchange does not influence the severity of DSS-provoked colitis which in this case looks to be determined by the host genetic background only.

The key in the understanding of the unique interactions between microbiota and immune system is the mutual interdependence of bacteria and their hosts. Nobody knows if this is the case for intestinal fungi; however, the initial data (with the emphasis on “initial”) coming from this report suggest something else. Investigators perform the assessment of murine intestinal mycobiome by sequencing and find that although there is enough diversity in the species arrangement, most data derive from a single organism – Candida tropicalis. This fungus is an opportunistic pathogen and authors confirm that it can play a role in the colitis development. Could intestinal fungi be just free riders?

Iliev ID, Funari VA, Taylor KD, Nguyen Q, Reyes CN, Strom SP, Brown J, Becker CA, Fleshner PR, Dubinsky M, Rotter JI, Wang HL, McGovern DP, Brown GD, & Underhill DM (2012). Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science (New York, N.Y.), 336 (6086), 1314-7 PMID: 22674328

Borrelia burgdorferi – the master manipulator

Who are the most accomplished immunologists in the world? The title may go to several pathogenic organisms that are apparently able to manipulate immune responses and do it in the way that puzzles many researchers. Bacterium Borrelia burgdorferi (the causative agent of Lyme disease) definitely belongs to the elite club. I have learnt that during infection it does not even try to hide away and assumes distinctively bold tactics as it migrates to the very hub of protective action – the draining lymph node. And there it does not sit quietly either since it can cue B cells to what it looks like the unusual (plus yet unexplained) proliferation which probably hinders the quality of ensuing protective response.

The link: http://www.jimmunol.org/content/188/11/5612.abstract

The discussed paper is a continuation of the report which was published by the same group last year (Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation. PLoS Pathog. 7: e1002066). Since I think it is important to combine the information from both papers I am going to summarize shortly the findings of that first publication before moving on to more recent results. Authors observed that when they infected mice with Borrelia using the natural route (tick’s bite) sick animals displayed the substantial enlargement of lymph nodes that were most adjacent to bite locations. In order to control the actual site of infection (ticks are living animals and they can move freely before starting their blood meal) as well as to avoid the direct use of culture-grown bacteria (which may stimulate the different type of immune response than bacteria from infested ticks) investigators have devised a modified infection procedure. Shortly, they injected immunocompromised mice (SCID) with culture-grown Borrelia and transplanted biopsies from such infected animals into the right tarsal joint of naive mice. This innovation has allowed focusing on the single draining lymph node while it exposed animals to host-adapted bacteria.

The particular problem that authors have tackled was how the Borrelia infection altered the right inguinal lymph node and whether there were any further modifications to the lymphatic architecture as the disease progressed. Investigators confirmed the rapid and intense accumulation of B cells in the draining lymph node and also noticed that this accumulation subsequently spread to more distant lymph nodes but not to the spleen. Such ensuing B cell response was critically dependent on the presence of live bacteria inside the lymph node yet quite surprisingly it occurred without any perturbations in the absence of MyD88. Apart from that, authors demonstrated that the immune reaction going on in affected lymph nodes was at least partially specific to Borrelia antigens.

In the follow-up paper researchers attempt to answer the question what is the role of CD4 T cells in the B cell accumulation prompted by Borrelia infection. They find out that CD4 T cells from affected lymph nodes do not increase their numbers as it happens to B cells yet they become activated along the course of disease. Nevertheless, the B cell buildup takes place without CD4 T cells as it did without MyD88. The anti-Borrelia antibody response, however, is weaker when there are no CD4 T cells around.

The overall picture of the immune response to Borrelia in the model that uses host-adapted bacteria (which mimics the natural infection) looks somehow paradoxical and misshapen. First pathogens invade the closest lymph node and seem to provoke there the massive B cell proliferation which disperses later to other lymph nodes. This proliferation is independent of mitogenic cues imparted by TLR signaling and it happens without CD4 T cell-driven costimulation as well. The specific anti-Borrelia antibody response (partially dependent on CD4 T cells) is then switched on but it gives the impression of being not completely normal, too. Authors show that the germinal center induction in lymph nodes is delayed and all germinal centers tend to decline very rapidly. However, plasma cells (which are thought to derive from the germinal center reaction) accumulate with kinetics suggesting that they are not generated in germinal centers located in lymph nodes. Investigators postulate that these plasma cells may originate from ectopic lymphoid tissues.

But it is the initial B cell accumulation that probably distorts the quality of anti-Borrelia immune response. Authors present data showing that this accumulation is indeed able to destroy the inherent organization of an affected lymph node. The question that I have is whether it happens because of sheer number of B cells or maybe through some defined B cell-specific antibody-independent effector mechanism like for example the release of a chemokine that interferes with the layout of a lymph node. Another interesting enigma is how Borrelia targets B cells and what receptor on B cell surface intercepts the signal.

Hastey CJ, Elsner RA, Barthold SW, & Baumgarth N (2012). Delays and diversions mark the development of B cell responses to Borrelia burgdorferi infection. Journal of immunology (Baltimore, Md. : 1950), 188 (11), 5612-22 PMID: 22547698

The intestinal role of NLRC4

The May issue of Nature Immunology contained an article that has described an intriguing mechanism of tolerance to microbiota without losing the ability to detect invading intestinal pathogens and switching on protection mechanisms when it comes to the defending. According to that report macrophages residing in the colon (but not from the bone marrow) remain hyporesponsive to TLR stimulation provided by commensal microbiota. However, the infection with Salmonella can provoke the same macrophages to process and secrete IL-1β cytokine in the manner that is dependent on NLRC4 inflammasome and caspase -1 activation (I have discussed this publication in one of my previous posts: https://memoryreactivation.wordpress.com/2012/05/22/mononuclear-phagocytes-and-the-intestinal-tolerance). The report I am discussing today is related to the above paper because it systematically analyzes the intestinal role of NLRC4. It turns out that there are substantial differences between consequences of deleting NLRC4 compared to effects of TLR5 deletion in conditions when both strains are presumed to harbor the same microbiota (both NLRC4 and TLR5 recognize flagellin – a dominant immune activator in the gut). These differences can be visible either in the healthy colon or in colitis development but not during Salmonella infection.

The link: http://www.nature.com/mi/journal/v5/n3/abs/mi20128a.html

Authors have shown earlier that the deletion of TLR5 caused severe changes in the interactions between host and intestinal commensals even in the absence of any challenge. Such perturbations can lead to the greater bacterial burden in the gut followed by the increase in pro-inflammatory indicators, colitis and eventually the tendency to develop metabolic syndrome diseases (Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5: Science. 2010; 328:228-31). Deletion of NLRC4, however, does not procure any spontaneously occurring physiological changes.

In addition, NLRC4 knockout mice do not display any major effect when they are given injections with anti-IL-10R antibody (the cytokine IL-10 is very important player in maintaining the intestinal tolerance and ablating IL-10 signaling often results in colitis). In contrast, animals with TLR5 or double TLR5/NLRC4 deletions develop colitis upon such treatment. Another way to inflict colitis is to expose the intestinal epithelium to a chemical called DSS which introduces damages to the gut barrier. Investigators show that NLRC4 knockouts similarly to mice with deleted TLR5 are more sensitive to DSS-driven colitis that the wild type strain.

The paper also examines the response against Salmonella infection in mice with NLRC4, TLR5 and double TLR5/NLRC4 deletions. Authors use two strategies – the first applies the procedure resulting in disease that is similar to infection in humans (by pretreating mice with streptomycin prior to bacterial exposure) and serves to examine early inflammatory events in colon and cecum. The second approach includes low-dose oral infection with several Salmonella strains to assess the effect of analyzed deletions on mice survival.

NLRC4 is involved the early detection of Salmonella, although it seems to work together with TLR5. Data show that the single removal of either NLRC4 or TLR5 does not render mice incapable to mount the inflammatory response to this pathogen. Only the double NLRC4/TLR5 deletion strain does not react to Salmonella. The secretion of IL-1β cytokine is also abolished only in the double deletion animals. Interestingly, all double deletion effects (no inflammation and no IL-1β secretion) are mirrored by MyD88 deletion which ablates the signaling to the majority of TLR receptors and the signaling to cytokines processed by NLRC4 inflammasome – IL-1β and IL-18. Authors use this fact to underscore the notion that flagellin (ligand for TLR5) is indeed the dominant immune activator in the gut. Finally, the protective role of NLRC4 is demonstrated by showing that NLRC4 deletion impairs survival to a flagellate strain of Salmonella. In contrast, no any difference between mice with NLRC4 knockout and wild type strain is seen when animals are infected with aflagellate bacteria.

It is hard to directly compare both papers because they have quite different scopes – the first studies only one colonic cell population whereas the other analyzes the overall immune response in the colon. But I think that they corroborate each other versions because unlike TLR5 NLRC4 looks indeed like the immune receptor which is not involved in dealing with microbiota under normal circumstances. However, it is the TLR5/NLRC4 axis that seems be critical in mounting the efficient defense against intestinal pathogens (because only the double TLR5/NLRC4 makes no response to Salmonella). The first paper shows that intestinal macrophages are hyporesponsive to TLR stimulation but they maintain the constitutive expression of pro-IL-1β (which is somehow diminished in germ-free mice). TLR5 is expressed on the surface of antigen presenting cells but also by intestinal epithelial cells whereas NLRC4 is present exclusively inside intestinal macrophages. Could colonic epithelial cells prime these macrophages to express pro-IL-1β when receiving signals through TLR5 from microbiota?

Carvalho FA, Nalbantoglu I, Aitken JD, Uchiyama R, Su Y, Doho GH, Vijay-Kumar M, & Gewirtz AT (2012). Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges. Mucosal immunology, 5 (3), 288-98 PMID: 22318495

The different chemokine profile in HIV-exposed seronegative persons

The studies on human population infected with or exposed to HIV have brought the description of several virus-refractory phenotypes. Among them are long-time non-progressors and HIV-exposed seronegative persons. The first group is able to control virus replication without the anti-retroviral therapy, maintain the normal CD4 T cell number and avoid the chronic immune activation that is normally associated with HIV infection. In consequence, long-time non-progressors can live with the presence of HIV for many years with minimal or without any ill effects. The second group is less widely known and comprises people who despite the persistent exposure to the virus do not become infected. In ordinary circumstances HIV gets into the body through mucosal surfaces at genital organs. HIV-exposed seronegative persons (HESN) appear to differ from the virus-sensitive population in terms of chemokine profile at the natural infection site.

The link: http://www.nature.com/mi/journal/v5/n3/abs/mi20127a.html

The study is conducted among Kenyan commercial sex workers divided into three categories. The experimental group includes HESN women, whereas control groups are HIV-1 negative women and HIV-1 infected patients. Authors analyze the cytokine/chemokine profile in the cervicovaginal lavage of each group. They detects that MIG and IP-10 (two IFN-γ inducible chemokines involved in the leukocyte trafficking) and cytokine IL-1α are expressed at lower level in the HESN cohort. Both chemokines are involved in the mucosal migration of activated CD4 T cells – the main HIV target. Hence one of HESN phenotype explanation might be that these people display the state of immune quiescence at their genital mucosa and simply do have enough number of activated CD4 T cells to become infected by virus.

To validate this point investigators examine plasma chemokine/cytokine profile in all studied groups as lymphocytes migrate to mucosal surfaces according to the chemokine gradient between blood and mucosa. They demonstrate that MIG levels in HESN group were higher in systemic compartments than at the genital mucosa whereas the HIV-1 negative population shows the opposite trend. Additionally, HESN subjects uniquely display the decreasing gradient for IP-10 from plasma to mucosal surfaces. The supportive data in this paper include the analysis of CXCR3 (the receptor bound by MIG and IP-10) on CD4 and CD8 T cells collected from the genital mucosa. Authors also study the expression of antiproteases in the genital tract as they are important factors regulating mucosal chemokine levels. It would be interesting to know what really drives the decreased chemokine levels in the genital tract of HESN.

J Lajoie, J Juno, A Burgener, S Rahman, K Mogk, C Wachihi, J Mwanjewe, F A Plummer, J Kimani, T B Ball, and K R Fowke (2012). A distinct cytokine and chemokine profile at the genital mucosa is associated with HIV-1 protection among HIV-exposed seronegative commercial sex workers Mucosal Immunology DOI: 10.1038/mi.2012.7

Mononuclear phagocytes and the intestinal tolerance

I already wrote a couple of entries about microbiota and the fact that our intestinal commensal bacteria do not stimulate aggressive response from the immune system. Most microorganisms share ligands recognized by innate receptors regardless of whether they are pathogens or symbionts. Therefore the way in which our immune system is viewed to operate – by recognition of conserved molecular patterns by antigen presenting cell populations and ensuing activation of immune response – does not explain well the “microbiota problem”. In fact the question how our body makes a distinction between “attack” vs. “hold on” options at mucosal surfaces still needs unraveling. I have found the report that makes an observation on the subject how intestinal tolerance could be maintained without compromising the need for appropriate response when endangered by infectious organisms. This publication suggests that gut-resident antigen presenting cells may be responsive to the presence of certain pathogen-indicating systems but not to ubiquitously present molecular conserved patterns.

The link: http://www.nature.com/ni/journal/v13/n5/full/ni.2263.html

Authors analyze cytokine release pattern (TNF-α, IL-6 and IL-1β) specific to a population coined as intestinal mononuclear phagocytes (iMPs), which are CD11b+ cells isolated from colonic/cecal lamina propria. Most iMPs bear macrophage marker F4/80. These intestinal antigen presenting cells do not respond by making cytokines to several TLR agonists or commensal bacteria but instead they are able to react to the pathogenic bacterium species – Salmonella. Their cytokine profile is also distinct from bone marrow-derived macrophages as they make only IL-1β but not TNF-α or IL-6. In contrast, bone marrow-derived macrophages produce uniformly TNF-α and IL-6 regardless of provided stimulation (TLR ligands or pathogenic bacterium).

IL-1β response by iMPs does not occur when cells are deficient for NLRC4 (cytosolic Nod-like receptor that forms part of inflammasome complex). It is also absent if Salmonella lacks type 3 secretion system (the apparatus that transports bacterial virulence factors into host cell) or flagellin. Developing this observation investigators provide molecular data that link the cleavage of pro-IL-1β into its active form with inflammasome activity (caspase-1 cleavage). Following the above finding, NLRC4-IL-1β axis is shown to be important for the protection against intestinal pathogenic bacterium in an in vivo model. Experimental infections with Salmonella that approximate human disease (by pretreating mice with streptomycin prior to infection) demonstrate worst survival rates for Nlrc4/ and Il1r/ mutants (however, this effect is strain-dependent as it takes place in BALB/c line but not C57BL/6 strain).

The major conclusion of this publication suggests the existence of a detection network that circumvents TLR signaling and relies on inflammasome activation by features unique to pathogens (like type 3 secretion system). However, I have a question that was not answered in the discussion part. Earlier this year the same group has shown that intestinal macrophages very similar to iMPs  (CD11b+F4/80+CD11c-/low) form the source of IL-1β secretion in response to microbiota (I wrote the entry about that publication few months ago – https://memoryreactivation.wordpress.com/2012/03/11/microbiota-il-1%CE%B2-and-th17/). In the paper I am discussing today it is demonstrated that iMPs do not respond by making IL-1β  to commensal bacteria but can be stimulated only by T3SS-possessing pathogenic bacterium. Could it be caused by anatomical differences as this paper studies colonic/cecal lamina propria population and the former investigates processes in small intestine?

Follow-up note: I have contacted the principal investigator with questions concerning both papers. I received comments confirming that these results were caused by different anatomical locations (small vs. large intestine).

Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P, Suzuki S, Shaw MH, Kim YG, & Núñez G (2012). NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nature immunology PMID: 22484733